Redox regulation of anoikis: reactive oxygen species as essential mediators of cell survival

Abstract

Proper attachment to the extracellular matrix (ECM) is essential for cell survival. The loss of integrin-mediated cell-ECM contact results in an apoptotic process termed anoikis. However, mechanisms involved in regulation of cell survival are poorly understood and mediators responsible for anoikis have not been well characterized. Here, we demonstrate that reactive oxygen species (ROS) produced through the involvement of the small GTPase Rac-1 upon integrin engagement exert a mandatory role in transducing a pro-survival signal that ensures that cells escape from anoikis. In particular, we show that ROS are responsible for the redox-mediated activation of Src that trans-phosphorylates epidermal growth factor receptor (EGFR) in a ligand-independent manner. The redox-dependent phosphorylation of EGFR activates both extracellular signal-regulated protein kinase and Akt downstream signalling pathways, culminating in degradation of the pro-apoptotic protein Bim. Hence, our results shed new light on the mechanism granting the adhesion-dependent antiapoptotic effect, highlighting a fundamental role of ROS-mediated Src regulation in ensuring anoikis protection.

Anoikis: an emerging hallmark in health and diseases

“…Hence, due to their high mobility, mesenchymal cells are usually more resistant to anoikis [46,47]. In addition, professionally non-adherent cells, such as haematopoietic mature cells and leukocytes, are protected from anoikis [48].…”

“…Indeed, ROS are key molecules that elicit pro-survival signals. Giannoni et al [48] observed that in cancer cells the oxidative intracellular milieu strongly correlates with induction of anoikis resistance; ROS production protects tumour cells from anoikis through the oxidation/activation of the tyrosine kinase Src, thus granting the activation of pro-survival pathways through a Src-dependent and ligand-independent phosphorylation of EGFR, which leads to Bim degradation. Furthermore, in human lung adenocarcinoma cells, Src activation compensates for the loss of cell-survival signals caused by disruption of cell-ECM interactions and contributes to anoikis resistance [92].…”

“…Really, activation of Src has been reported in various cancers characterized by anoikis resistance [48,69,114,115]. Actually, a crucial role is played by the modulation of PI3K-Akt signal pathway, regulated by PTEN-mediated dephosphorylation [116].…”

Redox regulation of anoikis resistance of metastatic prostate cancer cells: key role for Src and EGFR-mediated pro-survival signals

“…ROS are responsible for direct oxidation of the tyrosine kinase Src, thereby leading to its activation. The activated kinase in turn elicits a ligand-independent trans-phosphorylation of EGFR, that sequentially switches both ERK and Akt pathways, culminating in Bim degradation (Giannoni et al, 2008).…”

Integration of Autophagy and Anoikis Resistance in Solid Tumors

“…The phosphorylation of FAK by protein tyrosine kinase 6 (PTK6) also acts as an important mechanism in AI proliferation (Zheng et al, 2012). The ROS, which is constitutively high in metastatic cells, activates Src and further phosphorylates EGFR, subsequently leading to the phosphorylation of Akt and Erk, and finally, promoting the survival of cancer cells when losing ECM contact (Giannoni et al, 2008;Kim et al, 2012). The aforementioned researches suggest that the oncogenic regulations majorly positively contribute to the resistance of anoikis.…”